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18Q22.1-Qter Deletion and 4P16.3 Microduplication in a Boy With

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18Q22.1-Qter Deletion and 4P16.3 Microduplication in a Boy With Wang et al. Molecular Cytogenetics (2018) 11:55 https://doi.org/10.1186/s13039-018-0404-2 CASE REPORT Open Access 18q22.1-qter deletion and 4p16.3 microduplication in a boy with speech delay and mental retardation: case report and review of the literature Chunjing Wang1†, Huanhuan Ren1†, Huaifu Dong2, Meng Liang1,QiWu1 and Yaping Liao1* Abstract Background: Deletions involving the long arm of chromosome 18 have been associated with a highly variable phenotypic spectrum that is related to the extent of the deleted region. Duplications in chromosomal region 4p16.3 have also been shown to cause 4p16.3 microduplication syndrome. Most reported patients of trisomy 4p16.3 have more duplications, including the Wolf-Hirschhorn critical region (WHSCR). Here, we present a patient with speech delay and mental retardation caused by a deletion of 18q (18q22.1-qter) and terminal microduplication of 4p (4p16.3-pter) distal to WHSCR. Case presentation: The patient was a 23-month-old boy with moderate growth retardation, severe speech delay, mental retardation, and dysmorphic features. Single nucleotide polymorphism (SNP) array analysis confirmed an 11.2-Mb terminal deletion at 18q22.1 and revealed a 1.8-Mb terminal duplication of 4p16.3. Our patient showed clinical overlap with these two syndromes, although his overall features were milder than what had been previously described. Some dosage-sensitive genes on the 18q terminal deleted region and 4p16.3 duplicated region of the present case may have contributed to his phenotype. Conclusions: This is the first report of a patient with combined terminal deletion of 18q22.1 and duplication of 4p16.3. In this report, we provide clinical and molecular evidence supporting that the microduplication in 4p16.3, distal to WHSCR, is pathogenic. The coexistence of two chromosome aberrations complicates the clinical picture and creates a chimeric phenotype. This report provides further information on the genotype-phenotype correlation of 18q terminal deletion and 4p microduplication. Keywords: 18q22.1 deletion, 4p16.3 duplication, Speech delay, Mental retardation, Facial dysmorphisms Background dosage-sensitive genes and critical regions on 18q that con- Deletions of the long arm of chromosome 18 (18q deletion tribute to the clinical features have been identified, thereby syndrome, OMIM #601808) are common abnormalities in- providing a foundation for establishing the genotype- volving chromosome 18 [1]. Individuals with a terminal phenotype correlation for 18q deletions [1, 6]. 18q deletion display variable phenotypes, including short Terminal deletions of chromosome 4p cause Wolf- stature, microcephaly, characteristic dysmorphic facial fea- Hirschhorn syndrome (WHS, OMIM #194190). Dupli- ture, cleft lip/palate, delayed myelination, foot deformities, cations involving 4p16.3 have also been reported in hypotonia, congenital aural atresia (CAA), mental retard- several individuals, giving rise to a proposed 4p16.3 ation (MR), and genitourinary malformations [2–5]. Some microduplication syndrome [7, 8]. Larger imbalanced rearrangements on chromosome 4p in the form of * Correspondence: [email protected] – † deletions and duplications involving the Wolf Hirsch- Chunjing Wang and Huanhuan Ren contributed equally to this work. horn critical region (WHSCR) have defined clinical 1Department of Life Sciences, Bengbu Medical College, 2600 Donghai Avenue, Bengbu, Anhui 233030, People’s Republic of China features, such as developmental delay, delayed Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Wang et al. Molecular Cytogenetics (2018) 11:55 Page 2 of 7 psychomotor development, intellectual disability, and 593,997-66,735,890); and RP11-90E1, 182,823 bp, and craniofacial and skeletal malformations [9–12]. How- 18q12.3 (chr18:41,350,363-41,533,185). Images were cap- ever, the significance and clinical presentation of turedusingafluorescentmicroscope(LeicaDM5000B), patients with microduplication distal to WHSCR are and signals were analyzed using Leica CW 4000 software. not well understood. To the best of our knowledge, only two patients have been reported to date [8, 13]. SNP array analysis Here, we report another case of a 23-month-old boy Infinium OmniZhongHua-8 SNP arrays (Illumina, San with a 1.8-Mb duplication at 4p16.3 distal to the Diego, CA, USA) were utilized to analyze genome-wide WHSCR combined with an 11.2-Mb terminal deletion at copy number aberrations. DNA amplification, tagging, the 18q22.1, who presents with similar and different and hybridization were processed according to manufac- symptoms previously seen in trisomy 4p and 18q dele- turer’s protocols. Illumina’s iScan system was used to scan tion syndrome. This case provides further information the beadchips. Image data was analyzed using Illumina’s regarding the clinical features and genotype-phenotype GenomeStudio. correlation of 18q deletion and 4p16.3 microduplication. Results Case presentation The G-banding chromosomal analysis revealed a karyo- The patient was a 23-month-old boy who was referred for type of 46, XY, del (18) (q22) (Figs. 1a and b). The karyo- cytogenetic studies because of speech delay and mental types of his parents are normal. To investigate the retardation. He was born at 38 weeks gestation following deletion region of 18q, fluorescence in situ hybridization an unremarkable pregnancy by Caesarean section. His (FISH) analysis using chromosome 18 BAC probes was birth weight was 3.40 kg (<50th centile), and birth length performed. Data showed hybridization signals in the was 52 cm (>75th centile). At birth, he had an umbilical region of 18q22.1 (chr18:66,593,997-66,735,890) (Fig. 1c) hernia, which healed at 3 months of age. and no hybridization signal in the region of 18q23 The patient could sit at 8 months, and took his first (chr18:77,115,373-77,301,252) (Fig. 1d) and 18q22.3 steps at 18 months. At 23 months, his height was 90 cm (chr18:71,881,306-71,881,983) (Fig. 1e), indicating an (<75th centile), and his weight was 13 kg (<75th centile). 18q22 terminal deletion. To identify the size and pos- He cannot speak meaningful words and walked with ition of the chromosomal aberrations, we performed instability and large strides. Medical examination SNP array analysis. The results showed a terminal dele- revealed developmental delay, sensory integration dys- tion at 18q22.1 (Fig. 2a) and revealed the presence of a function, moderate MR, and reduced cognitive ability. duplication at 4p16.3 (Fig. 2b). The terminal deletion Additional physical features included hypotonia, a moon 18q22.1 was approximately 11.2 Mb (66,794,478– face, midface hypoplasia, deep-set eyes, epicanthal folds, 78,015,180) in size and the 4p16.3 duplication was a wide nasal bridge, a flat nose, a protrusible mouth, approximately 1.8 Mb (71,566–1,883,647) in size (UCSC short neck, and a longer fourth toe of the right foot. No genome browser, Human Assembly, GRCh37/hg19). significant defects such as cleft lip/palate, ears, heart, lung or genitourinary system were noted. Discussion Using conventional karyotyping, FISH, and SNP array Materials and methods analyses, we report a case involving a terminal deletion Karyotyping of 18q22.1 and duplication of 4p16.3. Patients with ter- For chromosome analysis, metaphase chromosomes were minal deletions of the long arm of chromosome 18 or obtained from peripheral blood lymphocytes after 72 h of microduplications of the short arm of chromosome 4 incubation and were prepared for GTG banding according display diverse phenotypes. The clinical phenotypes of to standard protocols. our patient show similarities and differences from previ- ously reported cases. Fish The 18q22 deletion syndrome is characterized by men- According to standard protocols, the cultured blood tal retardation and development delay, as well as a range lymphocytes of the patient were harvested to obtain meta- of physical anomalies, including microcephaly, short phase chromosomes. FISH analysis was performed with six stature, hearing loss, CAA, cleft palate with or without different chromosome 18 BAC probes; RP11-7H17, cleft lip (CL/CP), white matter abnormalities of the 185,880 bp, 18q23 (chr18:77,115,373-77,301,252); RP11- brain, hand and foot malformations. Several reports have 55 N14, 173,736 bp, 18p11.31 (chr18:2,744,753-2,918,488); explored the genotype-phenotype correlations of 18q22 RP11-53 N15, 678 bp, 18q22.3 (chr18:71,881,306-71,881, deletion syndrome. Recently, Cody et al. [6] viewed more 983); RP11-90 L7, 165,866 bp, 18q11.2 (chr18:23,355,089- than 350 individuals with 18q22 deletion syndrome and 23,520,954); RP11-79A24, 141,894 bp, 18q22.1 (chr18:66, classified 133 of a total of 196 confirmed genes on 18q Wang et al. Molecular Cytogenetics (2018) 11:55 Page 3 of 7 Fig. 1 Identification of chromosome 18 terminal deletion. a GTG banded karyotype of the case showing an aberration at distal 18q indicated by an arrow. b G-banding of chromosome 18 showing the deletion of 18q. c BAC-probes RP11-79A24 (orange) (18q22.1) (chr18:66,593,997-66,735,890) and RP11-90E1 (green) (18q12.3) (chr18:41,350,363-41,533,185) showing no deletion at 18q22.1 (chr18:66,593,997-66,735,890). d BAC-probes (green) (18q22.3) (chr18:71,881,306-71,881,983) and RP11-90 L7 (orange) (18q11.2) (chr18:23,355,089-23,520,954) revealing the deletion of 18q22.3.
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